Longitudinal studies have shown that childhood Attention Deficit/Hyperactivity Disorder (ADHD) and familial substance abuse appear to play an important role in the development of later Substance Use Disorders (SUD). Although available evidence suggests that abnormal reward processing is likely to mediate vulnerabilities for addiction, the functioning of the brain reward systems in at-risk individuals preceding the exposure to drugs remains largely unknown. Better understanding of the baseline characteristics of reward processing in drug- nave individuals at risk for later SUD is an important initial step in refining our knowledge of the neurobiological basis of addiction. Reward processing is further influenced by exposure to first-line treatments (e.g. methylphenidate (MPH)) for ADHD that also happen to be controlled substances. Several clinical studies have provided conflicting results about the relationship between adolescent SUD and stimulant treatment. Moreover, animal research has provided results suggesting that stimulants (e.g. methylphenodate (MPH)) may have a consistent ?sensitization? effects thus priming the brain reward system for enhanced responding to the rewarding effects of abusable substances whereas non-stimulants (e.g. atomoxetine (ATX)) may diminish drug self-administration. Many researchers have stipulates that stimulants and non-stimulants may have similar effects in humans. However, no studies have examined the purported different effects of stimulants vs. non- stimulants on the brain reward system utilizing a targeted biomarker approach linked to a model, which focuses on intermediate phenotypes. Such research could provide important knowledge regarding the biological basis of addiction vulnerability and aid in the development of preventive interventions. Our team has investigated baseline differences in activation of the brain reward system using functional neuroimaging in youth defined as having Low (e.g. ADHD only) and High (e.g. ADHD + comorbid ODD/CD + parental SUD) risks for subsequent SUD before initial exposure to abusable substances. We are in excellent position to further investigate the initial effects of MPH vs. ATX treatments on the activation patterns of the reward system. This proposal will test the hypotheses suggesting that stimulant and non-stimulant medications will have differential effects on the activation the brain reward system in the High Risk youth and that these differences in activation will be paralleled by changes in measures of reward sensitivity on various psychometric tests.. We believe that this protocol is uniquely innovative in its approach to study drug- nave children at the highest levels of risk thus providing an opportunity to delineate differential effects of medication treatment in relation to clinical risk. This research is also significant since it will be the first neuroimaging study to assess the biological correlates of the effects of stimulants on reward sensitivity in HR children, especially in relation to purported changes in reward processing.